Biomarker-driven molecular imaging probes in radiotherapy.

Background: Biomarker-driven molecular imaging has emerged as an integral part of cancer precision radiotherapy. The use of molecular imaging probes, including nanoprobes, have been explored in radiotherapy imaging to precisely and noninvasively monitor spatiotemporal distribution of biomarkers, potentially revealing tumor-killing mechanisms and therapy-induced adverse effects during radiation treatment. Methods: We summarized literature reports from preclinical studies and clinical trials, which cover two main parts: 1) Clinically-investigated and emerging imaging biomarkers associated with radiotherapy, and 2) instrumental roles, functions, and activatable mechanisms of molecular imaging probes in the radiotherapy workflow. In addition, reflection and future perspectives are proposed. Results: Numerous imaging biomarkers have been continuously explored in decades, while few of them have been successfully validated for their correlation with radiotherapeutic outcomes and/or radiation-induced toxicities. Meanwhile, activatable molecular imaging probes towards the emerging biomarkers have exhibited to be promising in animal or small-scale human studies for precision radiotherapy. Conclusion: Biomarker-driven molecular imaging probes are essential for precision radiotherapy. Despite very inspiring preliminary results, validation of imaging biomarkers and rational design strategies of probes await robust and extensive investigations. Especially, the correlation between imaging biomarkers and radiotherapeutic outcomes/toxicities should be established through multi-center collaboration involving a large cohort of patients.

A Double Network Composite Hydrogel with Self-Regulating Cu2+/Luteolin Release and Mechanical Modulation for Enhanced Wound Healing.

Designing adaptive and smart hydrogel wound dressings to meet specific needs across different stages of wound healing is crucial. Here, we present a composite hydrogel, GSC/PBE@Lut, that offers self-regulating release of cupric ions and luteolin and modulates mechanical properties to promote chronic wound healing. The double network hydrogel, GSC, is fabricated through photo-cross-linking of gelatin methacrylate, followed by Cu2+-alginate coordination cross-linking. On one hand, GSC allows for rapid Cu2+ release to eliminate bacteria in the acidic pH environment during inflammation and reduces the hydrogel's mechanical strength to minimize tissue trauma during early dressing changes. On the other hand, GSC enables slow Cu2+ release during the proliferation stage, promoting angiogenesis and biocompatibility. Furthermore, the inclusion of pH- and reactive oxygen species (ROS)-responsive luteolin nanoparticles (PBE@Lut) in the hydrogel matrix allows for controlled release of luteolin, offering antioxidant and anti-inflammatory effects and promoting anti-inflammatory macrophage polarization. In a murine model of Staphylococcus aureus infected wounds, GSC/PBE@Lut demonstrates exceptional therapeutic benefits in antibacterial, anti-inflammatory, angiogenic, and tissue regeneration. Overall, our results suggest that smart hydrogels with controlled bioactive agent release and mechanical modulation present a promising solution for treating chronic wounds.

Study on trade-offs and synergies of rural ecosystem services in the Tacheng-Emin Basin, Xinjiang, China: Implications for zoning management of rural ecological functions.

Rural areas are the main source of ecosystem services in arid and semi-arid areas, and ecosystem services are the background conditions for rural revitalization. In this study, the spatial pattern of key ecosystem services in the countryside was assessed, and the trade-offs and synergistic relationships among ecosystem services were investigated, using the Tacheng-Emin Basin in China as the study area. Finally, the types of ecological function zoning and development strategies for the countryside are proposed. The results showed that: (1) the area of ecological land was large, and the average land use intensity was 2.48, which belonged to the medium intensity. (2) The mean values of the six ecosystem services are all in the middle and lower classes, and the spatial distribution of the five ecosystem services is similar, except for food production. (3) Except for grain production, the other five ecosystem services showed positive feedback to elevation. The other five ecosystem services are synergistic, and there are trade-offs between grain production and other ecosystem services. In the nonlinear interaction mechanism of ecosystem services, the fluctuation constraint occupies the largest proportion. (4) At smaller spatial scales, there are more types of ecosystem service clusters. Combining the results of the study, the villages in the study area can be categorized into five types. This study formulates five priority levels of rural ecological revitalization and proposes different development recommendations for the sustainable development of each type of village. This study is helpful for the fine management of land resources and the revitalization of rural ecology and provides a reference for the sustainable development of ecosystem services in arid and semi-arid areas.

Programmed Cascade Polydopamine Nanoclusters for Pyroptosis-Based Tumor Immunotherapy.

Pyroptosis, an inflammatory cell death, plays a pivotal role in activating inflammatory response, reversing immunosuppression and enhancing anti-tumor immunity. However, challenges remain regarding how to induce pyroptosis efficiently and precisely in tumor cells to amplify anti-tumor immunotherapy. Herein, a pH-responsive polydopamine (PDA) nanocluster, perfluorocarbon (PFC)@octo-arginine (R8)-1-Hexadecylamine (He)-porphyrin (Por)@PDA-gambogic acid (GA)-cRGD (R-P@PDA-GC), is rationally design to augment phototherapy-induced pyroptosis and boost anti-tumor immunity through a two-input programmed cascade therapy. Briefly, oxygen doner PFC is encapsulated within R8 linked photosensitizer Por and He micelles as the core, followed by incorporation of GA and cRGD peptides modified PDA shell, yielding the ultimate R-P@PDA-GC nanoplatforms (NPs). The pH-responsive NPs effectively alleviate hypoxia by delivering oxygen via PFC and mitigate heat resistance in tumor cells through GA. Upon two-input programmed irradiation, R-P@PDA-GC NPs significantly enhance reactive oxygen species production within tumor cells, triggering pyroptosis via the Caspase-1/GSDMD pathway and releasing numerous inflammatory factors into the TME. This leads to the maturation of dendritic cells, robust infiltration of cytotoxic CD8+ T and NK cells, and diminution of immune suppressor Treg cells, thereby amplifying anti-tumor immunity.

Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

Branched glycopolymer prodrug-derived nanoassembly combined with a STING agonist activates an immuno-supportive status to boost anti-PD-L1 antibody therapy.

Despite the great potential of anti-PD-L1 antibodies for immunotherapy, their low response rate due to an immunosuppressive tumor microenvironment has hampered their application. To address this issue, we constructed a cell membrane-coated nanosystem (mB4S) to reverse an immunosuppressive microenvironment to an immuno-supportive one for strengthening the anti-tumor effect. In this system, Epirubicin (EPI) as an immunogenic cell death (ICD) inducer was coupled to a branched glycopolymer via hydrazone bonds and diABZI as a stimulator of interferon genes (STING) agonist was encapsulated into mB4S. After internalization of mB4S, EPI was acidic-responsively released to induce ICD, which was characterized by an increased level of calreticulin (CRT) exposure and enhanced ATP secretion. Meanwhile, diABZI effectively activated the STING pathway. Treatment with mB4S in combination with an anti-PD-L1 antibody elicited potent immune responses by increasing the ratio of matured dendritic cells (DCs) and CD8+ T cells, promoting cytokines secretion, up-regulating M1-like tumor-associated macrophages (TAMs) and down-regulating immunosuppressive myeloid-derived suppressor cells (MDSCs). Therefore, this nanosystem for co-delivery of an ICD inducer and a STING agonist achieved promotion of DCs maturation and CD8+ T cells infiltration, creating an immuno-supportive microenvironment, thus potentiating the therapy effect of the anti-PD-L1 antibody in both 4T1 breast and CT26 colon tumor mice.

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis.

To address the limitations of traditional photothermal therapy (PTT)/ photodynamic therapy (PDT) and real-time cancer metastasis detection, a pH-responsive nanoplatform (NP) with dual-modality imaging capability was rationally designed. Herein, 1 H,1 H-undecafluorohexylamine (PFC), served as both an oxygen carrier and a 19F magnetic resonance imaging (MRI) probe, and photosensitizer indocyanine green (ICG) were grafted onto the pH-responsive peptide hexahistidine (H6) to form H6-PFC-ICG (HPI). Subsequently, the heat shock protein 90 inhibitor, gambogic acid (GA), was incorporated into hyaluronic acid (HA) modified HPI (HHPI), yielding the ultimate HHPI@GA NPs. Upon self-assembly, HHPI@GA NPs passively accumulated in tumor tissues, facilitating oxygen release and HA-mediated cell uptake. Once phagocytosed by lysosomes, protonation of H6 was triggered due to the low pH, resulting in the release of GA. With near-infrared laser irradiation, GA-mediated decreased HSP90 expression and PFC-mediated increased ROS generation amplified the PTT/PDT effect of HHPI@GA, leading to excellent in vitro and in vivo anticancer efficacies. Additionally, the fluorescence and 19F MRI dual-imaging capabilities of HHPI@GA NPs enabled effective real-time primary cancer and lung metastasis monitoring. This work offers a novel approach for enhanced cancer phototherapy, as well as precise cancer diagnosis.

A bismuth-based double-network hydrogel-mediated synergistic photothermal-chemodynamic therapy for accelerated wound healing.

Multidrug-resistant bacterial infections present a significant challenge to wound healing. Non-antibiotic approaches such as photothermal therapy (PTT) and chemodynamic therapy (CDT) are promising but have suboptimal anti-bacterial efficacy. Herein, we developed a green bismuth-based double-network hydrogel (Bi@P-Cu) as a PTT/CDT synergistic platform for accelerated drug-resistant bacteria-infected wound healing. Bismuth (Bi) nanoparticles fabricated using a microwave method were used as a highly efficient and biocompatible PTT agent while the integration of a small amount of CDT agent Cu2+ endowed the hydrogel with excellent mechanical and self-healing properties, markedly increased photothermal efficiency, promoted cell migration ability, and negligible toxicity. Importantly, PTT enhanced the production of hydroxyl radicals in CDT and the destruction of bacterial cell membranes, which in turn enhanced the thermal sensitivity of bacteria. This synergistic anti-bacterial effect, together with the demonstrated capability to promote angiogenesis and anti-inflammation as well as enhanced fibroblast proliferation, led to accelerated wound healing in a full-thickness mouse model of resistant bacterial infection. This study provides an effective and safe strategy to eliminate drug-resistant bacteria and accelerate wound healing through green, non-antibiotic, double-network hydrogel-mediated synergistic PTT and CDT.

Bioorthogonal In Situ Polymerization of Dendritic Agents for Hijacking Lysosomes and Enhancing Antigen Presentation in Cancer Cells.

A low-generation lysine dendrimer, SPr-G2, responds to intracellular glutathione to initiate bioorthogonal in situ polymerization, resulting in the formation of large assemblies in mouse breast cancer cells. The intracellular large assemblies of SPr-G2 can interact with lysosomes to induce lysosome expansion and enhance lysosomal membrane permeabilization, leading to major histocompatibility complex class I upregulation on tumor cell surfaces and ultimately tumor cell death. Moreover, the use of the SPr-G2 dendrimer to conjugate the chemotherapeutic drug, camptothecin (CPT), can boost the therapeutic potency of CPT. Excellent antitumor effects in vitro and in vivo are obtained from the combinational treatment of the SPr-G2 dendrimer and CPT. This combinational effect also enhances antitumor immunity through promoting activation of cytotoxic T cells in tumor tissues and maturation of dendritic cells. This study can shed new light on the development of peptide dendritic agents for cancer therapy.

Dendritic Polymer-Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response.

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

Dendronized Polymer-Derived Nanomedicines for Mitochondrial Dynamics Regulation and Immune Modulation.

The effects of dendron side chains in polymeric conjugates on tumor penetration and antigen presentation are systematically examined. Three polymer-gemcitabine (Gem) conjugates (pG0-Gem, pG1-Gem, pG2-Gem) are designed and prepared. The pG2-Gem conjugate uniquely binds to the mitochondria of tumor cells, thus regulating mitochondrial dynamics. The interaction between the pG2-Gem conjugate and the mitochondria promotes great penetration and accumulation of the conjugate at the tumor site, resulting in pronounced antitumor effects in an animal model. Such encouraging therapeutic effects can be ascribed to immune modulation since MHC-1 antigen presentation is significantly enhanced due to mitochondrial fusion and mitochondrial metabolism alteration after pG2-Gem treatment. Crucially, the drug-free dendronized polymer, pG2, is identified to regulate mitochondrial dynamics, and the regulation is independent of the conjugated Gem. Furthermore, the combination of pG2-Gem with anti-PD-1 antibody results in a remarkable tumor clearance rate of 87.5% and a prolonged survival rate of over 150 days, demonstrating the potential of dendronized polymers as an innovative nanoplatform for metabolic modulation and synergistic tumor immunotherapy.

Nanoscale myelinogenesis image in developing brain via super-resolution nanoscopy by near-infrared emissive curcumin-BODIPY derivatives.

Understanding the intricate nanoscale architecture of neuronal myelin during central nervous system development is of utmost importance. However, current visualization methods heavily rely on electron microscopy or indirect fluorescent method, lacking direct and real-time imaging capabilities. Here, we introduce a breakthrough near-infrared emissive curcumin-BODIPY derivative (MyL-1) that enables direct visualization of myelin structure in brain tissues. The remarkable compatibility of MyL-1 with stimulated emission depletion nanoscopy allows for unprecedented super-resolution imaging of myelin ultrastructure. Through this innovative approach, we comprehensively characterize the nanoscale myelinogenesis in three dimensions over the course of brain development, spanning from infancy to adulthood in mouse models. Moreover, we investigate the correlation between myelin substances and Myelin Basic Protein (MBP), shedding light on the essential role of MBP in facilitating myelinogenesis during vertebral development. This novel material, MyL-1, opens up new avenues for studying and understanding the intricate process of myelinogenesis in a direct and non-invasive manner, paving the way for further advancements in the field of nanoscale neuroimaging.

Monitoring of Medical Wastewater by Sensitive, Convenient, and Low-Cost Determination of Small Extracellular Vesicles Using a Glycosyl-Imprinted Sensor.

The monitoring of small extracellular vesicles (sEVs) in medical waste is of great significance for the prevention of the spread of infectious diseases and the treatment of environmental pollutants in medical waste. Highly sensitive and selective detection methods are urgently needed due to the low content of sEVs in waste samples and the complex sample composition. Herein, a glycosyl-imprinted electrochemical sensor was constructed and a novel strategy for rapid, sensitive, and selective sEVs detection was proposed. The characteristic trisaccharide at the end of the glycosyl chain of the glycoprotein carried on the surface of the sEVs was used as the template molecule. The glycosyl-imprinted polymer films was then prepared by electropolymerization with o-phenylenediamine (o-PD) and 3-aminophenylboronic acid (m-APBA) as functional monomers. sEVs were captured by the imprinted cavities through the recognition and adsorption of glycosyl chains of glycoproteins on sEVs. The m-APBA molecule also acted as a signal probe and was then attached on the immobilized glycoprotein on the surface of sEVs by boric acid affinity. The electrochemical signal of m-APBA was amplificated due to the abundant glycoproteins on the surface of sEVs. The detection range of the sensor was 2.1 × 104 to 8.7 × 107 particles/mL, and the limit of detection was 1.7 × 104 particles/mL. The sensor was then applied to the determination of sEVs in medical wastewater and urine, which showed good selectivity, low detection cost, and good sensitivity.

Mitocytosis Mediated by an Enzyme-Activable Mitochondrion-Disturbing Polymer-Drug Conjugate Enhances Active Penetration in Glioblastoma Therapy.

The application of nanomedicines for glioblastoma (GBM) therapy is hampered by the blood-brain barrier (BBB) and the dense glioblastoma tissue. To achieve efficient BBB crossing and deep GBM penetration, this work demonstrates a strategy of active transcellular transport of a mitochondrion-disturbing nanomedicine, pGBEMA22-b-pSSPPT9 (GBEPPT), in the GBM tissue through mitocytosis. GBEPPT is computer-aided designed and prepared by self-assembling a conjugate of an amphiphilic block polymer and a drug podophyllotoxin (PPT). When GBEPPT is delivered to the tumor site, overexpressed γ-glutamyl transpeptidase (GGT) on the brain-blood endothelial cell, or the GBM cell triggered enzymatic hydrolysis of γ-glutamylamide on GBEPPT to reverse its negative charge to positive. Positively charged GBEPPT rapidly enter into the cell and target the mitochondria. These GBEPPT disturb the homeostasis of mitochondria, inducing mitocytosis-mediated extracellular transport of GBEPPT to the neighboring cells via mitosomes. This intracellular-to-intercellular delivery cycle allows GBEPPT to penetrate deeply into the GBM parenchyma, and exert sustainable action of PPT released from GBEPPT on the tumor cells along its penetration path at the tumor site, thus improving the anti-GBM effect. The process of mitocytosis mediated by the mitochondrion-disturbing nanomedicine may offer great potential in enhancing drug penetration through malignant tissues, especially poorly permeable solid tumors.

Chitosan-based hydrogel dressings for diabetic wound healing via promoting M2 macrophage-polarization.

A long-term inflammatory phase of diabetic wounds is the primary cause to prevent their effective healing. Bacterial infection, excess reactive oxygen species (ROS), especially failure of M2-phenotype macrophage polarization can hinder the transition of diabetic wounds from an inflammation phase to a proliferation one. Herein, a chitosan-based hydrogel dressing with the ability of regulating M2 macrophage polarization was reported. The PAAc/CFCS-Vanillin hydrogel dressing was synthesized by one step thermal polymerization of catechol-functionalized chitosan (CFCS), acrylic acid, catechol functional methacryloyl chitosan­silver nanoparticles (CFMC-Ag NPs) and bioactive vanillin. The PAAc/CFCS-Vanillin hydrogel possessed sufficient mechanical strength and excellent adhesion properties, which helped rapidly block bleeding of wounds. Thanks to CFCS, CFMC-Ag NPs and vanillin in the hydrogel, it displayed excellent antibacterial infection in the wounds. Vanillin helped scavenge excess ROS and regulate the levels of inflammatory factors to facilitate the polarization of macrophages into the M2 phenotype. A full-thickness skin defect diabetic wound model showed that the wounds treated by the PAAc/CFCS-Vanillin hydrogel exhibited the smallest wound area, and superior granulation tissue regeneration, remarkable collagen deposition, and angiogenesis were observed in the wound tissue. Therefore, the PAAc/CFCS-Vanillin hydrogel could hold promising potential as a dressing for the treatment of diabetic chronic wounds.

An Electrochemiluminescent Sensor Based on Glycosyl Imprinting and Aptamer for the Detection of Cancer-Related Extracellular Vesicles.

Cancer-related extracellular vesicles (EVs) are considered important biomarkers for cancer diagnosis because they can convey a large amount of information about tumor cells. In order to detect cancer-related EVs efficiently, an electrochemiluminescence (ECL) sensor for the specific identification and highly sensitive detection of EVs in the plasma of cancer patients was constructed based on dual recognitions by glycosyl-imprinted polymer (GIP) and aptamer. The characteristic glycosyl Neu5Ac-α-(2,6)-Gal-ß-(1-4)-GlcNAc trisaccharide on the surface of EVs was used as a template molecule and 3-aminophenylboronic acid as a functional monomer to form a glycosyl-imprinted polymer by electropolymerization. After glycosyl elution, the imprinted film specifically recognized and adsorbed the EVs in the sample, and then the CD63 aptamer-bipyridine ruthenium (Aptamer-Ru(bpy)) was added to combine with the CD63 glycoprotein on the extracellular vesicle's surface, thus providing secondary recognition of the EVs. Finally, the EVs were quantitatively detected according to the ECL signal produced by the labeled bipyridine ruthenium. When more EVs were captured by the imprinted film, more probes were obtained after incubation, and the ECL signal was stronger. Under the optimized conditions, the ECL signal showed a good linear relationship with the concentration of EVs in the range of 9.5 × 102 to 9.5 × 107 particles/mL, and the limit of detection was 641 particles/mL. The GIP sensor can discriminate between the EV contents of cancer patients and healthy controls with high accuracy. Because of its affordability, high sensitivity, and ease of use, it is anticipated to be employed for cancer early detection and diagnosis.

Homomultivalent Polymeric Nanotraps Disturb Lipid Metabolism Homeostasis and Tune Pyroptosis in Cancer.

Genetic manipulations and pharmaceutical interventions to disturb lipid metabolism homeostasis have emerged as an attractive approach for the management of cancer. However, the research on the utilization of bioactive materials to modulate lipid metabolism homeostasis remains constrained. In this study, heptakis (2,3,6-tri-O-methyl)-ß-cyclodextrin (TMCD) is utilized to fabricate homomultivalent polymeric nanotraps, and surprisingly, its unprecedented ability to perturb lipid metabolism homeostasis and induce pyroptosis in tumor cells is found. Through modulation of the density of TMCD arrayed on the polymers, one top-performing nanotrap, PTMCD4, exhibits the most powerful cholesterol-trapping and depletion capacity, thus achieving prominent cytotoxicity toward different types of tumor cells and encouraging antitumor effects in vivo. The interactions between PTMCD4 and biomembranes of tumor cells effectively enable the reduction of cellular phosphatidylcholine and cholesterol levels, thus provoking damage to the biomembrane integrity and perturbation of lipid metabolism homeostasis. Additionally, the interplays between PTMCD4 and lysosomes also induce lysosomal stress, activate the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasomes, and subsequently trigger tumor cell pyroptosis. To sum up, this study first introduces dendronized bioactive polymers to manipulate lipid metabolism and has shed light on another innovative insight for cancer therapy.

Oxidase-like manganese oxide nanoparticles: a mechanism of organic acids/aldehydes as electron acceptors and potential application in cancer therapy.

Identifying the underlying catalytic mechanisms of synthetic nanocatalysts or nanozymes is important in directing their design and applications. Herein, we revisited the oxidation process of 4,4'-diamino-3,3',5,5'-tetramethylbiphenyl (TMB) by Mn3O4 nanoparticles and revealed that it adopted an organic acid/aldehyde-triggered catalytic mechanism at a weakly acidic or neutral pH, which is O2-independent and inhibited by the pre-addition of H2O2. Importantly, similar organic acid/aldehyde-mediated oxidation was applied to other substrates of peroxidase in the presence of nanoparticulate or commercially available MnO2 and Mn2O3 but not MnO. The selective oxidation of TMB by Mn3O4 over MnO was further supported by density functional theory calculations. Moreover, Mn3O4 nanoparticles enabled the oxidation of indole 3-acetic acid, a substrate that can generate cytotoxic singlet oxygen upon single-electron transfer oxidation, displaying potential in nanocatalytic tumor therapy. Overall, we revealed a general catalytic mechanism of manganese oxides towards the oxidation of peroxidase substrates, which could boost the design and various applications of these manganese-based nanoparticles.

Nanomedicine Combats Drug Resistance in Lung Cancer.

Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer.

Enzyme-Responsive Branched Glycopolymer-Based Nanoassembly for Co-Delivery of Paclitaxel and Akt Inhibitor toward Synergistic Therapy of Gastric Cancer.

Combined chemotherapy and targeted therapy holds immense potential in the management of advanced gastric cancer (GC). GC tissues exhibit an elevated expression level of protein kinase B (AKT), which contributes to disease progression and poor chemotherapeutic responsiveness. Inhibition of AKT expression through an AKT inhibitor, capivasertib (CAP), to enhance cytotoxicity of paclitaxel (PTX) toward GC cells is demonstrated in this study. A cathepsin B-responsive polymeric nanoparticle prodrug system is employed for co-delivery of PTX and CAP, resulting in a polymeric nano-drug BPGP@CAP. The release of PTX and CAP is triggered in an environment with overexpressed cathepsin B upon lysosomal uptake of BPGP@CAP. A synergistic therapeutic effect of PTX and CAP on killing GC cells is confirmed by in vitro and in vivo experiments. Mechanistic investigations suggested that CAP may inhibit AKT expression, leading to suppression of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway. Encouragingly, CAP can synergize with PTX to exert potent antitumor effects against GC after they are co-delivered via a polymeric drug delivery system, and this delivery system helped reduce their toxic side effects, which provides an effective therapeutic strategy for treating GC.